The invention relates to methods of forming nanoparticles using semiconductor manufacturing infrastructure, and more specifically to fabrication of particles having a defined shape and size using lithographically defined templates to mold the nanoparticles.
Nanoparticles have received significant interest for both diagnostic and therapeutic medical applications. Nanoparticles are particularly well suited for drug delivery applications. Many therapeutic agents, including drug molecules, siRNA, and proteins, have a short half-life and are quickly degraded or removed from circulation within the body. Other drug candidates exhibit poor solubility characteristics. Nanoparticles can serve as delivery vehicles, thereby mitigating the challenges of drug delivery and enhancing therapeutic activity by extending drug half-life, improving drug solubility, reducing immunogenicity, and controlling drug release (Shi, J.; Votruba, A. R.; Farokhzad, O. C.; Langer, R. NanoLett. 2010, 10, 3223-3230). The nanoparticles can be organic (derived from either small molecules or polymers), inorganic, or an organic-inorganic hybrid material. The therapeutic agents can be attached to or encapsulated within the nanoparticle. Moreover, the nanoparticles can actively or passively target specific cells to enable selective delivery.
The majority of nanotechnology-based therapeutics for drug delivery approved by the Food and Drug Administration are composed of a drug incorporated within, or attached to, a polymer, micelle, or liposome (Wagner, V.; Dullarrt, A.; Bock, A. K.; Zweck, A. Nat. Biotechnol. 2006, 24, 1211-1217. Davis, M. E.; Chen, Z.; Shin, D. M. Nat. Rev. Drug Discovery 2008, 7, 771-782). The size of these drug delivery vehicles is important. Most drug delivery vehicle complexes vary in size from tens to hundreds of nanometers. In the case of targeting tumor tissues, the size of the nanoparticle drug delivery agent should ideally be smaller than 150 nm in order to passively diffuse into the tumor cells via the enhanced permeability and retention (EPR) effect (Matsumura, Y.; Maeda, H. Cancer Res. 1986, 46, 6387-6392).
There is a growing understanding to those knowledgeable in the art that in addition to particle size, the particle shape is also an important parameter for potential drug delivery applications. The shape of the particle can control the nature of the interaction with the cell surface, and thus can be used to enable cell targeting based on shape (Champion, J. A.; Katare, Y. K.; Mitragotri, S. J. Control. Release 2007, 121, 3-9). Moreover, controlling both the size and shape can affect degradation rate, transport, targeting, and internalization of the drug delivery vehicle.
Despite the importance of particle size and shape in drug delivery, there exist only a few methods to fabricate non-spherical particles reproducibly on a large scale. Mitragotri has developed an approach which embeds a polymeric particle within a second polymeric film, and then uses heat combined with compression or extension to afford particles with non-spherical shapes (Champion, J. A.; Mitragotri, S. Proc. Natl. Acad. Sci. U.S. A. 2006, 103, 4930-4934). DeSimone has developed an imprint-based process for fabricating templates which can be used to mold precursors into a particle (Euliss, L. E.; DuPont, J. A.; Gratton, S.; DeSimone, J. Chem. Soc. Rev. 2006, 35, 1095-1104; J. M. Desimone, et al., US 2010/0151031A1).
Additional methods are needed to fabricate nanoparticles for therapeutic applications.